Therapeutics New visions in ophthalmic drug development Over the last 10 years we have seen the introduction of several new ‘ophthalmology only’ pharmaceutical products emerge such as Trusopt (dorzolamide, Merck) and Xalatan (latanoprost, Pharmacia). Innovative products such as these have driven much of the ophthalmic pharmaceutical growth, outpacing the older products that were often developed for ophthalmology via other therapeutic areas.With the ophthalmic pharmaceutical sector currently at around $5 billion worldwide, the continued growth is likely to be driven by even more first-in-class entries in ophthalmology.Two areas that are especially poised for explosive growth are dry eye and retinal disease, in which many new therapeutic approaches are currently in development. ecent changes and restructuring in corpo- ing of EyeTech, which raised $100 million for a By Dr Benjamin R. rate aspects of the ophthalmology market- ‘biotech’ anti-angiogenesis project for treating reti- Yerxa, Dr Ward M. R place will likely influence the future of nal disease in August 2001. Other biotechnology Peterson and Robin ophthalmic drug discovery. For example, in 1999 and pharmaceutical companies, such as S.Whitsell Bausch and Lomb, a company with few propri- Genentech, Inspire, ISTA and Eli Lilly have invest- etary prescription products, restructured itself by ed significant cash and resources into their selling its Miracle Ear hearing aid, Charles River advanced stage ophthalmic products. Shifts like and Ray Ban divisions. It then essentially used the these in ophthalmic pharmaceutical R&D are proceeds to purchase the European-based eye care shaping the future of eye care. company Groupe Chauvin for $228 million in cash. This movement helped to reposition Bausch Emerging areas and Lomb for growing its global prescription drug Several disease areas of ophthalmology are under- business. In July 2002 Allergan spun out its optical served by prescription pharmaceuticals. The medical device business to create Advanced largest unmet medical needs are dry eye disease Medical Optics, transforming Allergan into a spe- and a number of retinal diseases, such as age-relat- cialty pharmaceutical ‘pure play’. On March 21, ed macular degeneration, diabetic retinopathy and 2002 Nestle spun out Alcon in an IPO valued at retinitis pigmentosa. These conditions have been about $2.3 billion, creating the world’s largest under-served primarily because of their complex independent eye care company. Other transactions etiology and progression, which has eluded the have raised attention, such as the start-up financ- development of new drugs. In recent years, insight Drug Discovery World Winter 2002/3 51 Therapeutics Figure 1 Cross-section of the eye highlighting ocular surface Main lacrimal structures.The eye seen in gland cross-section reveals the main and accessory lacrimal glands that secrete bulk fluid and proteins, and the meibomian glands in the eyelids that Accessory produce lipids.The conjunctival lacrimal glands surface joins with the cornea and surrounds the inner eye lids, producing mucus and additional fluid to directly Conjunctiva hydrate the ocular surface Cornea Meibomian glands into disease mechanisms and identifiable drug tar- effecting as many as 12 million people in the US gets has resulted in the emergence and develop- alone1. Despite the numerous over-the-counter ment of a number of promising drug candidates artificial tears available as tear substitutes, these that are now in late-stage clinical studies, particu- aqueous lubricant solutions provide short-lived larly for the treatment of dry eye disease, age-relat- relief of symptoms, but do not address the under- ed macular degeneration and diabetic retinopathy. lying problems associated with the disease, nor do they have significant effects on ocular surface Dry eye health. Currently there are no approved, pharma- Dry eye syndrome is a multifaceted disease charac- cologically active drugs for treating dry eye disease; terised by symptoms of chronic irritation and however, recent approaches to treating dry eye dis- inflammation (itching, burning, pain and gritty ease in clinical development include targeting sensations) and ocular surface damage (as evi- inflammation, secretion and hormones. denced by corneal and conjunctival staining)4. The health and integrity of the ocular surface are main- Anti-inflammatory tained by the fluid and protein secreting main and A major component of dry eye disease is the per- accessory lacrimal glands, the lipid producing mei- sistent ocular surface inflammation that occurs, bomian glands and the fluid and mucin secreting either primarily due to autoimmune diseases such conjunctival epithelium (Figure 1). as Sjögren’s syndrome, or secondarily as a result of Epidemiological studies of dry eye show an chronic dryness and irritation. Regardless of the increased prevalence in post-menopausal women, cause, inflammatory infiltrates release cytokines 52 Drug Discovery World Winter 2002/3 Therapeutics that accumulate on the ocular surface and slowly ued for only several days or a few weeks at a time. degrade and remodel the epithelium, leading to the In Sjögren’s disease patients, non-preserved corti- hallmark sign of dry eye: a compromised ocular costeroid treatment resulted in a desired decrease surface that can be assessed by corneal and con- of corneal staining and a resolution of filamentary junctival staining techniques. Anti-inflammatory keratitis. Some patients also experienced relief interventions have shown some promising results. from the symptom of irritation3. Restasis (cyclosporine A, Allergan), a topical immunosuppressant that reduces ocular surface Secretagogues inflammation, is currently undergoing a Phase 3 Since dry eye is a disease of impaired ocular surface clinical trial to confirm positive results from previ- hydration as measured by a marked decrease in tear ous Phase 3 trials2. Allergan received an approv- secretion particularly from the lacrimal glands, it is able letter from the FDA on August 24, 1999 and reasonable to expect that a pro-secretory approach expects to launch Restasis in late 2003. In would be beneficial. Despite the obviousness of November 2002, Debiopharm announced that a such an approach, secretagogue-based therapeutic more water-soluble prodrug of cyclosporine A may development for dry eye has not been successful. be developed as a treatment for dry eye. Another For example, muscarinic secretagogues (M3 recep- anti-inflammatory drug that is used systemically tor agonists) approved for dry mouth, such as for similar indications as cyclosporine, called FK- Salagen4 (pilocarpine, MGI) and Evoxac5 (cevime- 506 (tacrolimus, Fujisawa), is being developed out- line, Daiichi), have not been proven efficacious in side Asia for dry eye disease by Sucampo treating dry eye. This may be due in part to the mul- Pharmaceuticals. Tacrolimus for treating dry eye tiple components of ocular surface secretion, ie it is disease is currently in Phase 2 in Europe with plans a combination of glandular and epithelial secretion for future US studies in the coming years. that is under both neural regulation and nonadren- Topical corticosteroids, although generally con- ergic, noncholinergic control. traindicated for chronic use due to the risk of The most advanced secretagogue in clinical increases in IOP and cataract formation, have been development is INS365 Ophthalmic Solution used as ‘pulse therapy’ in which dosing is contin- (diquafosol, Inspire), a P2Y2 nucleotide receptor Ta b le 1: Dry eye medications in development COMPANY COMPOUND TYPE OF PRESUMED MEDICATION PHASE OF DEVELOPMENT Alcon 15-HETE Secretagogue Phase 2 Allergan Restasis Anti-inflammatory Phase 3 Allergan Androgen Tear Hormone Phase 3 Inspire INS365 Secretagogue Phase 3 Otsuka OPC-12759 Secretagogue Phase 2 Sucampo FK-506 Anti-inflammatory Phase 2 Drug Discovery World Winter 2002/3 53 Therapeutics Ta b le 2:Wet AMD medications in development COMPANY COMPOUND MEDICATION PRESUMED TYPE PHASE OF DEVELOPMENT Alcon Anecortave Acetate Steroid subtenons Phase 3 injection EyeTech Macugen Anti-angiogenesis Phase 3 intravitreal injection Genaera Squalamine Anti-angiogenesis Phase 1 Genentech RhuFab Anti-VEGF intravitreal Entering Phase 3 injection Miravent SnET2 PDT Post-Phase 3 Oxigene Combretastatin Vascular targeting agent Entering Phase 1/2 Novartis, QLT Visudyne PDT Approved agonist. This nucleotide stimulates primarily con- in Phase 2 in the US, although results of patient tri- junctival epithelial secretion of salt, fluid and als have not been reported yet. mucin and possibly lipid secretion from the meibo- mian gland, thereby making up the principal layers Hormone replacement of the tear film. The conjunctival secretion can be Since dry eye is most common in post-menopausal stimulated with INS365 to provide normal tear women, the link to hormonal changes has been volumes even in animals in which the lacrimal studied extensively. Hormone replacement therapy glands have been removed6. INS365 is currently in by itself, however, has not been correlated with Phase 3 clinical testing in the US, although the decreased dry eye. In fact, the opposite appears to company recently reported that the FDA would be true9. Despite the epidemiological puzzle, consider an NDA filing based on the completed researchers at the Aborn Eye Research Center in studies to date. Inspire expects to launch INS365 in New York, are currently investigating a propri- the US in early 2004 with its partner Allergan.